Method of combatting gastric ulceration

ABSTRACT

Bismuth subsalicylate co-administered with anti-inflammatory drugs combats gastric ulceration associated with such drugs.

This invention is concerned with a method for combatting gastric ulceration. In particular it is concerned with the use of bismuth subsalicylate to combate the ulcerogenic propensity of widely-used anti-inflammatory drugs.

Commonly used drugs such as aspirin, phenylbutazone, indomethacin, or ibuprofen, while exetrmely valuable for their anti-inflammatory and analgesic effects, are ill suited for long term use because of their tendency to cause gastric ulceration in th host receiving them.

It has now been discovered that bismuth subsalicylate when co-administered perorally with anti-inflammatory drugs such as those aforementioned combats gastric ulceration. Thus, gastric hemorrhagic lesion formation was induced in male Wistar rats by dosing 24-hour fasted animals with a 100 % ulcerogenic does (UD₁₀₀) of an anti-inflammatory drug concomitantly with various dose levels of bismuth subsalicylate. Four hours later, the stomachs were removed and mucosae examined for hemorrhagic lesions and an ED₅₀ value obtained by finding that dose of bismuth subsalicylate which inhibited the mean number of lesions by 50%.

The results are set forth in the following table:

                                      Table I                                      __________________________________________________________________________     Peroral Protective ED.sub.50 Values of Bismuth Subsalicylate                   in Reducing Mean Number of Gastric Hemorrhagic Lesions                         in Response to Anti-Inflammatory Drugs                                         __________________________________________________________________________                                    Mean No.                                                                             Bismuth                                                              No. of Lesions                                                                           Subsalicylate                                                  Dose  of  per   ED.sub.50 Value.sup.b                      Drug Combination.sup.a                                                                             (mg/kg)                                                                              Rats                                                                               Stomach                                                                              mg/kg                                     __________________________________________________________________________     Aspirin.sup.c + H.sub.2 O (control)                                                                 --    28  4.6                                             Aspirin + Bismuth Subsalicylate                                                                     17.5  7   4.1                                             Aspirin + Bismuth Subsalicylate                                                                     43.8  7   2.3   58.6                                      Aspirin + Bismuth Subsalicylate                                                                     87.5  7   2.1                                             Aspirin + Bismuth Subsalicylate                                                                     109.4 7   2.0                                             Aspirin + Bismuth Subsalicylate                                                                     153.0 7   0.5                                             Phenylbutazone.sup.d + H.sub.2 O (control)                                                          --    26  8.1                                             Phenylbutazone + Bismuth Subsalicylate                                                              4.4   6   6.1                                             Phenylbutazone + Bismuth Subsalicylate                                                              17.5  6   5.5   23.6                                      Phenylbutazone + Bismuth Subsalicylate                                                              21.9  7   4.9                                             Phenylbutazone + Bismuth Subsalicylate                                                              26.3  6   3.2                                             Phenylbutazone + Bismuth Subsalicylate                                                              43.8  6   1.8                                             Indomethacin.sup.e + H.sub.2 O (control)                                                            --    7   3.6                                             Indomethacin +  Bismuth Subsalicylate                                                               43.8  8   1.9   39.4                                      Indomethacin + Bismuth Subsalicylate                                                                37.5  7   0.9                                             Indomethacin + Bismuth Subsalicylate                                                                262.5 7   0.9                                             Ibuprofen.sup.f + H.sub.2 O (control)                                                               --    7   8.9                                             Ibuprofen + Bismuth Subsalicylate                                                                   4.4   7   6.1   11.0                                      Ibuprofen + Bismuth Subsalicylate                                                                   17.5  7   3.1                                             Ibuprofen + Bismuth Subsalicylate                                                                   43.8  7   2.7                                             __________________________________________________________________________      .sup.a Bismuth subsalicylate or distilled water administered in                combination with each listed anti-inflammatory drug.                           .sup.b Obtained by the Litchfield-Wilcoxon Method using the percentage         inhibition of mean number of lesions from control and then finding the         dose giving 50% inhibition.                                                    .sup.c UD100 = 200 mg/kg - 28 of 28 rats with gastric hemorrhagic lesions      .sup.d UD100 = 150 mg/kg - 26 of 26 rats with gastric hemorrhagic lesions      .sup.e UD100 = 10 mg/kg - 7 of 7 rats with gastric hemorrhagic lesions.        .sup.f UD100 = 100 mg/kg - 7 of 7 rats with gastric hemorrhagic lesions. 

The use of bismuth subsalicylate concomitantly with anti-inflammatory drugs has no adverse effect thereon. That the anti-inflammatory property of aspirin, phenyblutazone, indomethacin or ibuprofen was not impaired by the co-administration of bismuth subsalicylate was demonstrated using the standard carrageenin rat paw edema assay [Winter et. al. Proc. Soc. Exp. Bio. Med. 111:544 (l962)]. Thus, concomitant administration of the protective ED₅₀ of bismuth subsalicylate with the anti-inflammatory ED₅₀ of aspirin, phenylbutazone, indomethacin or ibuprofen was carried out in the 24-hour fasted male Wistar rat. The percent inhibition of edema formation at 4 and 6 hours after carrageenin administration was determined.

The results are shown in the following table:

                  Table 2                                                          ______________________________________                                         Anti-Inflammatory Activity in the Carrageenin-Induced                          Paw Edema Assay in Rats                                                        ______________________________________                                                     ED.sub.50      % Inhibition of                                                 Values                                                                               No. of   Edema Formation.sup.b                                 Treatment.sup.a                                                                            mg/kg   Rats     4 hr   6 hr                                     ______________________________________                                         Aspirin       167.sup.c                                                        +             +       8        40     23                                       Distilled H.sub.2 O (control)                                                                -                                                                Aspirin       167                                                              +             +       8        65     48                                       Bismuth Subsalicylate                                                                        58.6                                                             Phenylbutazone                                                                               204.sup.c                                                        +             +       8        52     41                                       Distilled H.sub.2 O                                                                          -                                                                Phenylbutazone                                                                               204                                                              +             +       8        65     48                                       Bismuth Subsalicylate                                                                        23.6                                                             Indomethacin  10.sup.c                                                         +             +       10       58     45.5                                     Distilled H.sub.2 O                                                                          -                                                                Indomethacin  10                                                               +             +       10       61.5   48.5                                     Bismuth Subsalicylate                                                                        39.4                                                             Ibuprofen     52.1                                                             +             +       16       44     40                                       Distilled H.sub.2 O                                                                          -                                                                Ibuprofen     52.1                                                             +             +       16       52     53                                       Bismuth Subsalicylate                                                                        11.0                                                             Distilled H.sub.2 O                                                                          -                                                                +             +       8        11     14                                       Bismuth Subsalicylate                                                                        23.6                                                                           or                                                                             58.6    8        11     20                                       ______________________________________                                          .sup.a Drug combinations administered 60 minutes before the injection of       carrageenin.                                                                   .sup.b Compared to control (nondrug-treated) hindpaw 4 and 6 hours after       carrageenin administration.                                                    .sup.c Anti-inflammatory ED.sub.50 value.                                

The anti-inflammatory drugs are commercially available in number of pharmaceutical dosage forms for oral administration as is bismuth subsalicylate. 

What is claimed is:
 1. The method of combatting gastric ulceration in a host receiving perorally an anti-inflammatory agent of the group of aspirin, phenylbutazone, indomethacin or ibuprofen which consists in similarly co-administering to said host an amount of bismuth subsalicylate sufficient to combat the gastric ulcerogenic propensity of said anti-inflammatory agent. 